Shoelson, Steven , MD, PhD
Circulating monocytes as targets of salicylate: biomarkers for response and potential mediators of pathogenesis
General Research Subject: Type 2 Diabetes
Focus: Clinical Therapeutics/New Technology\Pharmacologic Treatment of Diabetes or its Complications, Complications\Macrovascular-Cellular Mechanisms of Atherogenesis in Diabetes
Type of Grant: Clinical Translational Research
Project Start Date: January 1, 2012
Project End Date: December 31, 2014
We are developing a new approach for treating patients with type 2 diabetes (T2D) using salicylate (salsalate), a simple and safe anti-inflammatory drug long used for treating joint pain. The NIH-funded TINSAL-T2D trials, being conducted at 21 sites across the country, are establishing blood glucose and lipid lowering effects in patients with T2D. We hypothesized that salsalate would also improve risk for atherosclerosis and are testing this in a separate NIH-funded trial (TINSAL-CVD) in which 278 subjects will receive salsalate vs. placebo for 30 months duration. We wish to take advantage of the fact that the TINSAL-CVD trial is being conducted one site (Joslin/BIDMC) to test the effects of salsalate on circulating patient white blood cells (monocytes). Recent evidence suggests that 1) specific types of monocytes influence risk for T2D and heart disease, and 2) salsalate increases ratios of 'good vs. bad' monocytes in the blood, which may alter disease progression. Our approach is highly cost-effective as it capitalizes on the multimillion dollar TINSAL-CVD trial to supply patient white blood cells. We collect the white blood cells during patient visits, rush them to the lab to purify, stabilize and freeze the live blood cells for future analyses, conduct very detailed analyses of monocyte activity, and determine how this correlates with salsalate treatment and disease status, including blood glucose, insulin, HbA1c, lipids and atherosclerosis (plaque burden). The results of these studies will help us understand pathogenesis in T2D and response mechanisms for salsalate and potentially other anti-inflammatory therapies.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and or/curing diabetes?
Our studies attempt to determine why weight gain and obesity are unhealthy and promote diabetes and associated heart disease. We have found that inflammation, the body's normal response to infection, is also activated by weight gain and obesity, albeit to lesser degrees than is seen in acute infection. We have therefore realized that insulin resistance, type 2 diabetes and cardiovascular disease have immunological underpinnings similar to those seen for type 1 diabetes. This discovery has provided us with multiple avenues of attack, both in basic science terms for a better understanding and clinically to identify pharmacological routes for reversal. Studies outlined in this application couple our basic and clinical expertise in a true bench-to-bedside and bedside-to-bench approach. Importantly for patients with diabetes, we are evaluating salsalate, a cheap and safe drug that can be used today in patients with diabetes to test whether 'anti-inflammatory' approaches provide improved control. To date the answer is yes. In this study we are collecting blood samples from patients treated with salsalate and we will analyze their circulating monocytes. We have chosen to look at monocytes because they are the precursors of tissue resident macrophages and because salicylate affects the inflammatory status of monocytes in preclinical studies. We therefore expect to identify at a minimum, a new circulating marker for salicylate treatment. But it is also possible that the monocytes we are examining are involved more directly in disease pathology and that the anticipated changes in monocyte phenotype will reflect or predict disease modification.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
We are developing new glucose lowering treatments for patients with type 2 diabetes, which also appear to have substantial effects in complications associated with both type 2 and type 1 diabetes. In fact, the preclinical animal data are sufficiently good that we have also initiated larger clinical trials in patients with cardiovascular disease, independent of diabetes. We are very interested in looking at the ability of these new therapeutic avenues to diminish risk for complications in type 1 diabetes as well, including microvascular complications. It is therefore possible that salsalate or are newer version of it may provide improvements in both glucose control and complications in patients with diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
My professional goal over the last >30 years has been to understand the molecular underpinnings of diabetes and its complications, and to use this information to guide the development of better therapies. Studies in the lab including those funded by this award will help to ensure that these aspirations are fulfilled.
In what direction do you see the future of diabetes research going?
I hope to see a continuing increase in translational research as we continue to improve our more basic understanding of the pathophysiology in type 2 diabetes and its complications. We also foresee new studies into the use of our anti-inflammatory approaches to target both microvascular and macrovascular complications in type 1 diabetes. I hope that the ADA helps to sponsor an increasing amount of translational/clinical research.
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